Differential cholesteryl ester accumulation in two human vascular smooth muscle cell subpopulations exposed to aggregated LDL: effect of PDGF-stimulation and HMG-CoA reductase inhibition Original Research Article

Vascular smooth muscle cells (VSMC) are a major component of atheromatous plaque and they exhibit a high heterogeneity in morphology and proliferative activity. Two cell subpopulations from the media of human pulmonary artery were isolated according to the kinetics of outgrowth from the explants; the first wave of cell outgrowth (VSMC-I) and the second wave (VSMC-II) were separately cultured. They were characterized by premitotic DNA synthesis ([3H]thymidine incorporation) and cholesterol synthesis ([14C]acetate incorporation). DNA and cholesterol synthesis were approximately 13- and 5-fold, respectively, higher in VSMC-I than in VSMC-II. When these subpopulations were exposed to 100 μg/ml of aggregated low density lipoproteins (agLDL), their cholesteryl ester (CE) content increased 4.3-fold over that induced by native LDL. The increase in CE induced by native or agLDL was approximately 2.7-fold higher in VSMC-I than in VSMC-II. These results suggest that agLDL uptake is related, at least in part, to the cellular proliferative status. Platelet derived growth factor (PDGF) did not increase agLDL uptake in any subpopulation, although it efficiently promoted proliferative activity in both cell types and increased native LDL uptake and cholesterol synthesis in VSMC-II. Simvastatin strongly inhibited CE accumulation from agLDL in VSMC-I, either unstimulated or PDGF-stimulated (>80% inhibition). In contrast, it only blocked agLDL uptake in PDGF stimulated VSMC-II (50% inhibition). Our results indicate that the quantitative effect of simvastatin on CE accumulation from agLDL is dependent on phenotypic cell characteristics and it can be modulated in response to mitogenic stimulus.